Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is characterized by a selective loss of motor neurons, resulting in progressive muscle weakness and paralysis, as well as swallowing and speech difficulties. Oxidative stress, metabolic dysfunction, and neuroinflammation are well-known hallmarks of ALS. Knowing this, researchers at the VIB-KU Leuven Center for Cancer Biology decided to target a group of enzymes called EGLNs, metabolic sensors that regulate both cellular inflammation and metabolism. Their research led by Ludo Van Den Bosch, PhD, professor, demonstrated that downregulating EGLN2 protects motor neurons and can mitigate ALS symptoms in different animal models.
Their findings are published in Cell Reports in an article titled, “Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response.”
“…Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of Egln2 protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS,” the researchers wrote. “Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of EGLN2 restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling.”
Previously, the lab of Peter Carmeliet, MD, PhD, professor, from the VIB-KU Leuven Center for Cancer Biology explored the role of the EGLN2 enzyme in cells experiencing low oxygen levels. The research demonstrated that inhibiting EGLN2 protected muscle cells, liver cells, and cortical neurons against oxidative stress.
The researchers discovered that downregulating EGLN2 protects motor neurons and can mitigate the ALS phenotype in both zebrafish and mouse models. They also found that EGLN2 influences the pro-inflammatory cascade in astrocytes, a type of brain cell that supports motor neurons.
“We used a multi-model approach to investigate the effects of EGLN2 in different cell types,” said Christine Germeys, first author of the study and a doctoral student. “We included zebrafish, mice, and induced pluripotent stem cells (iPSCs) from an ALS patient and used single-nuclei RNA sequencing to understand the underlying processes behind EGLN2 regulation.”
“Targeting EGLN2 could represent a promising therapeutic strategy for ALS,” added Van Den Bosch. “While further research is needed, this discovery brings us closer to understanding how to slow or prevent this devastating disease.”
